Binding of to dystrophin impairs the membrane trafficking of Nav1.5 protein and increases ventricular arrhythmia susceptibility.

Dystrophin is a critical interacting protein of Nav1.5 that determines its membrane anchoring in cardiomyocytes. Long noncoding RNAs (lncRNAs) are involved in the regulation of cardiac ion channels, while their influence on sodium channels remains unexplored. Our preliminary data showed that lncRNA- homolog 1 () can bind to dystrophin, which drove us to investigate if can regulate sodium channels by interfering with dystrophin. Western blot and immunofluorescent staining showed that cardiomyocyte-specific transgenic overexpression of (-TG) reduced the membrane distribution of dystrophin and Nav1.5 in cardiomyocytes. Meanwhile, peak was reduced in the hearts of -TG mice than wild-type (WT) controls. The opposite data of western blot, immunofluorescent staining and patch clamp were collected from cardiomyocyte conditional knockout (-cKO) mice. Moreover, increased ventricular arrhythmia susceptibility was observed in -TG mice in vivo and ex vivo. The conservative fragment of inhibited membrane distribution of dystrophin and Nav1.5, and promoted the inducibility of ventricular arrhythmia. Strikingly, activation of transcription by dCas9-SAM system in -TG mice rescued the impaired membrane distribution of dystrophin and Nav1.5, and prevented the occurrence of ventricular arrhythmia. Furthermore, was increased in transaortic constriction (TAC) induced failing hearts, which promoted the inducibility of ventricular arrhythmia. And the expression of is regulated by hydroxyacyl-CoA dehydrogenase subunit beta (hadhb), which binds to and decreases its stability. The human homologue of inhibited the membrane distribution of Nav1.5 in human iPS-differentiated cardiomyocytes. The findings provide novel insights into the mechanism of Nav1.5 membrane targeting and the development of ventricular arrhythmias.